Dihydroxyoleandiene diesters

ABSTRACT

New esters are obtained by the acylation of 3,30-dihydroxyolean11,13(18)-diene with unsaturated alcohols. The new compounds have valuable anti-inflammatory properties.

United States Patent 1 1 Turner 1 Sept. 2, 1975 DIHYDROXYOLEANDIENE DIESTERS [75] Inventor: John Cameron Turner, West Wickham, England [73] Assignee: Biorex Laboratories, Limited,

England 22 Filed: Mar. 29, 1973 21 App1.N0.:346,947

[30] Foreign Application Priority Data Apr. 11, 1972 United Kingdom 16665/72 [52] U.S. C1. 260/482 R; 260/410; 260/484 B;

260/483; 260/485 L; 260/486 R; 260/487; 260/488 B; 424/31 1; 424/312; 424/313; 424/314 [51] Int. Cl. C07C 35/44; C07C 69/40; C07C101/18;A61K 31/215 [58] Field of Search 260/488 B, 485 L, 410,

260/487 R, 482, 488 B, 485 L, 410

OTHER PUBLICATIONS MousseronCanet et 21]., Bull. Soc. Chim. France, No. 1, pp. 245-249 (1969).

Primary ExaminerDonald G. Daus Assistant ExaminerDiana G. Rivers Attorney, Agent, or Firm-Wenderoth, Lind & Ponack [57] ABSTRACT New Esie'rs are oBiifiea'byth iation of 3 ,30-dihydroxyolean-ll,13(18)-diene with unsaturated alcohols. The new compounds have valuable antiinflammatory properties.

6 Claims, No Drawings DIHYDROXYOLEANDIENE DIESTERS BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The new esters according to the present invention are compounds of the general formula:

CH R

wherein R, and R which maybe the same or different, are acyl radicals derived from saturated or unsaturated, unsubstituted or substituted mono-, dior polycarboxylic acids, and wherein any carboxylic acid groups present in R and/or R are optionally salified with nontoxic inorganic or organicbases.

DETAILED DESCRIPTION OF THE INVENTION Examples of substituents which maybe present in R, and R include halogen atoms, amino groups and monoand disubstituted amino groups, for example, cyclic amino, monoand dialkylamino and monoand diarylamino groups,

The radicals R and R each contain preferably up to 20 carbon atoms and more preferably up to: 12 carbon atoms. Examples of acids from which the acyl radicals R and R can be derived include acetic acid, mon0-, di-and trichloroacetic acid, mono-, diand trifluoroacetic acid, propionic acid,,butyric acid, caproic acid, palmitic acid, stearic acid, acrylic acid, crotonic acid, angelic acid, tiglic acid, oleic acid, geranic acid, linoleic acid, tetrolic acid, malonic acid, succinic acid, glutaric acid, sebacic acid, maleic acid, fumaric acid, tartronic acid, malic acid, oxalacetic acid, tartaric acid and citric acid.

The new glycyrrhetinic acids according to the present invention can be prepared by acylating the compound of the formula:

, ca oa by methods of acylationin use or described in the literature.

Thus, the acyl derivatives may be prepared by using anhydrous carboxylic acids or the anhydrides thereof, preferably in the presence of an appropriate solvent at an elevated temperature. Acyl derivatives of polybasic organic acids in which at least one carboxylic acid group of the organic acid remains free, are preferably prepared by refluxing the organic acid with the compound (II) in an organic solvent or by reaction of an acid anhydride with thecompound (II) in pyridine solution. Salts of such derivatives can be prepared by neutralisation with a non-toxic inorganic or organic base. As examples of non-toxic inorganic bases, there may be mentioned alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates. Specific examples of inorganic salts according to the present invention include the sodium, potassium, magnesium, calcium, aluminium, zinc, manganese and iron salts. As examples. of non-toxic organic bases, there may i be mentioned the aliphatic, aromatic and heterocyclic amines.

When the compounds obtained contain halogen in R and/or R these can, if desired, be reacted with ammonia or with a primary or secondary amine to replace the halogen atom by an unsubstituted or monoor disubstituted amine group.

The following Examples are given for the purpose of illustrating the present invention:

EXAMPLE 1 I EXAMPLE 2 A solution of 10 g. 3,30-dihydroxyolean-l 1,1 3( l 8)- diene in 500 ml. dry chloroform was cooled in an icebath to 0C. To this were added 25 ml. N,N- diethylaniline, followed by the dropwise addition of 15 ml. chloroacetyl chloride. The reaction mixture was thereafter stirred for 6 hours at ambient temperature, the successively washed with water, dilute acid and aqueous sodium bicarbonate. After drying, the solvent was evaporated and the residue was taken up in 300 ml. benzene, filtered through a thick pad of g. alumina and further eluted with 300 ml. benzene. After evaporation of the benzene, the residue was crystallised from a mixture of ethanol and chloroform to give 12 g. 3,30- di-(chloroacetyl)-olean-l l,l3( l8)-diene, which had a melting point of 197 I98C.; [04],, 3l(c. 1% in chloroform).

"8 hours with 20 g. succinic anhydride. The reaction mixture was then poured into a mixture of dilute hydrochloric acid and'ice and stirred for minutes. The precipitate obtained was' filtered off, washed withwater' dried and dissolved in chloroformand ether 1:2).

The solution was then treated with charcoal, filtered and=coneentrated Upon cooling, 3,3() -dihemisuccinylol'ean-l l-',l 3'( l 8 )-'diene precipitated out. It was recrystallised from chloroform-ether and then had-a melting point of203204C; llb 3l(c. l in chloroform-)zjThe yield was" 11.5 g.

. EXAMPLE 4 Tl-0,325 g. 3,30-dihemisuceinyl-olean-l 1,1 3( l 8 )-diene (see Example 3) were suspended in 100 ml. methanol and mixedwith a solution of 1.28 g. sodium hydroxide in -50 ml;methanol. The solution. was then adjusted to pH 8 and diluted with 500 ml. acetone. The deposit obtained upontcooling was filtered off. There were thus obtained lO g. 3,30-dihemisuccinyl-olean-1l,'l3(l 8)- 1 diene disodium salt, which had .a meltingpointabove 280C. (dec.); [04] l9(c. 0.5.in-methanol).

I 4 I EXAMPLE 5 I 2b fiil. lauroyl chloride were added, while cooling, to a solution of 6.5 g. 3,30-dihydroxy-olean- 11,1 3 l 8)- diene in 50 ml. pyridine. The reaction was left to stand at 20C. for 20 hours and at 80C. for 30 minutes. After cooling, it was poured into a mixture of ice and hydrochloric acid, with vigorous stirring. The mixture was extracted with ether, the-ethereal extractv was washed with water-andtwith an, aqueous solution of sodiumbicarbonate and dried and thereafter evaporated to dryness..- The residuaL-oil was taken up in 300 ml. petroleumether, filtered thro'ugha-column which hadbeen filled .with 250 g. alumina in petroleum ether and further eluted with 300 ml. petroleum ether. The eluate obtained was concentratedto a small volume andleft to crystallise at l0C. After further recrystallisations, there was obtained colourless and pure 3,3 O-dilaurylolean .-,ll,l3(l8 )-diene, which had a melting point of 40 41C.; [a],, 20 (0. 1% in chloroform).

EXAMPLE 6 A mixture of 10.5 g. 3,3O-di-(chloroacetyl)-0leanl 1,1 3( l 8)-diene (see Example 2), 3 g. sodium carbonate, 10 ml. diethylamine and 150 ml. benzene was heated under reflux, while stirring, for 7 hours and then left to stand overnight at ambient temperature. Water was added to the reaction mixture, the benzene layer wasseparated off and then washed with water-dried and evaporated to dryness. The residue .was crystallised from a mixture of benzene, and petroleum ether. After recrystallisation from thesamesolvent mixture, there were obtained 10.5 g. of colourless. 3,30-di- (N,N-diethylaminoacetyU -olean-l l,l3( l8) -diene, which had a melting pointof l 27- 128C, la) 3() (c. 1% in chloroform), l

EXAMPLE 7 v A mixture of 8 3i30-dihydroxy-olean-l l,l3( l8)- diene and 400 mlfdry chloroform was cooled to 0C. and 12 ml. trifluoroacetic anhydride were added dropwise, while stirring. When the addition was completed, ml. cold water were added and, after 10 minutes, the chloroform layer was separated off, washed with an aqueous solution of sodium bicarbonate and water, dried and evaporated to dryness. The residue was crystallised from methanol to give 1 l g. 3,30-di-(tri IfluoroacetyU-olean l l,l3(l8)-diene, which had a melting point of 159- 160C; 0 1,, chloroform). I v

The present invention also includes within its scope pharmaceutical compositions containing the new compounds of general formula (1). These pharmaceutical compositions can be administered orally or parenterally in admixture with a solid or liquid pharmaceutical carrier. v Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid compositions, one of the new esters is admixed with at least one inert diluent, such as calcium carbonate, starch, alginic acid or lactose. The compositions may also comprise, as is normal practice,

additional substances other than inert diluents, for example, lubricating agents, such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents, such compositions may also comprise adjuvants, such as wetting and Suspension agents, and sweetening and flavouring agents.

The compositions according tothe present invention, for oral administration, include capsules of absorbable material, such as gelatine, containing one of the new derivatives, with or without the addition of diluents or excipients.

Preparations according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending media include propylene'glycol, polyethylene glycol, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. These compositions may also contain adjuvants, such as wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through bacteria-retaining filters, by incorporation into the compositions of sterilising agents, by irradiation or' by heating. They may also be produced in the form of sterile solid compositions, which can be dissolved in sterile water orsome other sterile injectable medium immediately before use. 5

.The percentage of active material in the compositions of the present invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage for the desired'therapeutic efect shall be obtained. In general, the preparations of the present invention should be administered orally ir parenterallyto humans to give 10 to 1000 mg, preferably 50 500 mg. of active substance per day.

The following Examples illustrate pharmaceutical compositions according to the present invention:-

EXAMPLE 8 250 mg. tablets are prepared containing:

3.3U-diucctyl-ulcan-l L1 3( lX)dicnc 50 mg. starch 100 mg. lactose 95 mg.

magnesium stcaratc 5 mg.

EXAMPLE 9 400 mg. tablets are prepared containing:

3.3()-hemisuccinyl-olezm-l l. l 3( 18 dicne. disodium salt starch lactose magnesium stearutc IOU mg. 130 mg. I60 mg.

ll) mg.

The compositions according to Examples 8 and 9 are I intended for oral administration to humans for the treatment of inflammatory conditions.

I claim: 1. A compound of the formula:

wherein R and R; which may be the same or different are acetyl substituted by l to 3 chlorine or fluorine atoms. diethylamino or carboxymethyl, the carboxy group of which is free or is in the form of a non-toxic salt.

2. 3,30-Di-(chloroacetyl)-olean-l 1,1 3( l 8 )-diene.

3. 3,30-Dihemisuccinyl-olean-l 1,1 3( 18 )-diene.

4. Disodium salt of 3,30-dihemisuccinyI-oleanll l3( l 8)-diene.

5. 3,30-Di(N,N-diethylaminoacetyl)-0leanll,l3( l8 )-diene.

6. 3,30-Di-(trifluoroacetyl)-olean-l l,l3( I8)-diene. 

1. A COMPOUND OF THE FORMULA:
 2. 3,30-Di-(chloroacetyl)-olean-11,13(18)-diene.
 3. 3,30-Dihemisuccinyl-olean-11,13(18)-diene.
 4. Disodium salt of 3,30-dihemisuccinyl-olean-11,13(18)-diene.
 5. 3,30-Di(N,N-diethylaminoacetyl)-olean-11,13(18)-diene.
 6. 3,30-Di-(trifluoroacetyl)-olean-11,13(18)-diene. 